EBV has been detected in epithelial cells in a new type of oral leukoplakia known as "hairy" leukoplakia (HLP). HLP is a harbinger for the development of the acquired immunodeficiency syndrome (AIDS). In contrast to most EBV-associated diseases, in HLP the infection is permissive of EBV replication. We have shown that both EBV Type l and 2 are replicating in HLP tissue and that superinfection with multiple strains of EBV occurs within the lesion and may contribute to the pathology. We have also determined that recombination and the generation of new EBV variants and defective EBV genome is a consistent feature of HLP. These data suggest that coinfection with two strains of lesser pathogenicity could result in the creation of a more pathogenic variant. We have shown that the strains of EBV which are replicating on the tongue in HLP may infect the peripheral blood. The presence of defective variants in the PBL of one patient demonstrates the possible infectivity of these viral variants and reveals the importance of HLP as a source for PBL infection. The consistent detection of defective genome and the presence of specific strains of EBV suggest that these virally determined factors contribute to the pathogenesis of HLP. The proposed studies will identify and characterize the strains of EBV which are replicating on the tongue in HLP and the strains which we present in the peripheral blood to determine the relationship between oral and peripheral blood reservoirs of infection. This will reveal whether HLP results from reactivated latent infection or represents an acute lytic process which is induced by superinfection with exogenous strains. In addition, potentially lytic or epithelial-trophic isolates of EBV will be captured for biologic and biochemical characterization. The proposed studies of viral expression in the HLP tissue and the effects of expression of specific viral genes in the infected epithelial cell lines will identify the viral determinants of this pathology. HLP provides a unique opportunity to further characterize oral EBV infection at the molecular level. This knowledge will illuminate the complex interaction of EBV with the immune system, further our understanding of oral manifestations of EBV reactivation, and the viral determinants of disease.